The present invention relates to pharmaceutical compositions and methods for treating glutamate-mediated diseases, disorders and conditions, particularly anxiety, anxiety disorders and memory impairment, using NAALADase inhibitors.
Anxiety disorders afflict over 23 million Americans. These people are tormented by panic attacks, obsessive thoughts, flashbacks, nightmares or countless frightening physical symptoms. Classes of drugs which are prescribed for the treatment of anxiety disorders include the benzodiazepines (such as diazepam) and buspirone hydrochloride. Although the benzodiazepines have achieved widespread acceptance since their introduction in the 1960's, their use is restricted due to their adverse side effects, in particular their tendency to induce dependence. While lacking the dependence-inducing side effects of the benzodiazepines, buspirone hydrochloride has a slow onset of action (about 4 weeks). Thus, there is a need for new pharmaceutical compositions and methods for treating anxiety and anxiety disorders.
Excessive activation of glutamate receptors has been implicated in anxiety and anxiety disorders. Significantly higher glutamate plasma levels have been detected in patients with mood disorders than in comparison subjects. In social interaction tests on rats, the blocking of basal glutamate excitation elicited anxiolytic-like effects.
It is widely published that glutamate modulators possess anxiolytic properties. In animal models of anxiolytic activity, NMDA antagonists reduced separation-induced ultrasonic vocalizations in rat pups, antagonized the suppressive effects of punishment on locomotor activity in the four-plate test on mice, enhanced exploration in the open arms of an elevated plus maze by rats, and blocked anxiety responses elicited by GABAA receptor blockade in the basolateral amygdala of rats; AMPA/kainate antagonists increased the percentage of entries of rats into the open arms of an elevated plus maze, and caused a dose-dependent increase of punished drinking behavior in a conflict-suppressed drinking test on rats; AMPA antagonists normalized pathologically increased electromyogram (EMG) activity in the hind limb extensor muscles of rats; mGluR antagonists produced a dose-dependent anticonflict effect in a conflict drinking Vogel test on rats; and mGluR agonists exhibited anxiolytic effects on mice in the fear potentiated startle and elevated plus maze models.
Studies also suggest that the pharmacological effect of anxiolytic agents is mediated through the glutamatergic system. In an intact neuronal circuit of a model extrahypothalamic CNS area, systemic injection and local application of progesterone suppressed glutamate excitation. Microdialysis shows that anxiogenic beta-carboline significantly increases glutamate efflux in the prefrontal cortex of rats. Reports also indicate that the anxiolytic effects of riluzole are mediated by the blockade of glutamate transmission. Concordantly, the inhibition of glutamate synthesis has been proposed as a possible mechanism for the anxiolytic activity of gabapentin.
Excessive activation of glutamate receptors has also been implicated in neurodegenerative disorders (e.g., Alzheimer's disease, Huntington's disease and AIDS encephalopathy) and in the generation of long-term potentiation, which is regarded as an electrophysiological manifestation of learning and memory. Specifically, the NMDA subtype of glutamate receptor appears to be involved in learning processes because the NMDA antagonist 2-amino-5-phosphono-pentanoate (AP5) selectively impairs learning and blocks long-term potentiation in rats. It has thus been proposed that deterioration in glutamatergic systems might account for impairment in cognitive function observed in aged animals or in Alzheimer's disease.
Recent studies have implicated NAALADase in the pathogenesis of glutamate-mediated disorders. Lesion studies on rat and neuropathological studies on post-mortem tissue from patients with amyotrophic lateral sclerosis (ALS) indicate large decreases of N-acetylaspartate (NAA) and N-acetylaspartylglutamate (NAAG) tissue concentrations occurring in association with neuronal degeneration, and increases of NAA and NAAG in cerebal spinal fluid (CSF) from patients with ALS. Concordantly, abnormal NAAG levels and NAALADase activity have also been observed in post-mortem prefrontal and limbic brain tissue of schizophrenic patients.
Autopsy studies also suggest a strong correlation between NAAG/NAA and Alzheimer's disease. In post-mortem brain tissue, NAA and NAAG levels were found to be selectively decreased in brain areas (hippocampus and amygdala) affected by Alzheimer's disease pathology.
Although not limited to any one particular theory, it is believed that NAALADase inhibitors block glutamate release pre-synaptically. The inventors have discovered that the glutamate blocking activity of NAALADase inhibitors has direct therapeutic applications for the pharmacotherapy of glutamate-mediated diseases, disorders and conditions, including without limitation anxiety, anxiety disorders and neurodegenerative diseases. Since neurodegenerative diseases are one of the leading causes of memory impairment, the inventors theorize that NAALADase inhibitors may be also beneficial in the treatment of memory impairment.
Most research and development activity to date have focused on blocking post-synaptic glutamate receptors with compounds such as NMDA antagonists, glycine antagonists, and other post-synaptic excitatory amino acid (EAA) receptor blockers. Unfortunately, these agents produce severe toxicities even under normal conditions, thus limiting their clinical use.
By contrast, NAALADase inhibitors inhibit glutamate release presynaptically without interacting with post-synaptic glutamate receptors. Since NAALADase inhibitors do not appear to alter basal glutamate levels, they may be devoid of the behavioral toxicities associated with post-synaptic glutamate antagonists.
Until a few years ago, only a few NAALADase inhibitors had been identified and they were used in non-clinical research. Examples of these compounds include general metallopeptidase inhibitors such as .omicron.-phenanthroline, metal chelators such as EGTA and EDTA, and peptide analogs such as quisqualic acid and .beta.-NAAG. These compounds either have toxic side effects or are incapable of being administered in pharmaceutically effective amounts. In view of the broad range of potential applications, there is a need for new NAALADase inhibitors and pharmaceutical compositions and methods of using the same.